NM_003854.4:c.437G>T

Variant names:

• chr2-102192068-G-T
• NM_003854.4:c.437G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003854.4(IL1RL2):​c.437G>T​(p.Cys146Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IL1RL2 NM_003854.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.47
• Publications: 0 publications found

Genes affected

IL1RL2 (HGNC:5999): (interleukin 1 receptor like 2) The protein encoded by this gene is a member of the interleukin 1 receptor family. An experiment with transient gene expression demonstrated that this receptor was incapable of binding to interleukin 1 alpha and interleukin 1 beta with high affinity. This gene and four other interleukin 1 receptor family genes, including interleukin 1 receptor, type I (IL1R1), interleukin 1 receptor, type II (IL1R2), interleukin 1 receptor-like 1 (IL1RL1), and interleukin 18 receptor 1 (IL18R1), form a cytokine receptor gene cluster in a region mapped to chromosome 2q12. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003854.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL1RL2	NM_003854.4	MANE Select	c.437G>T	p.Cys146Phe	missense	Exon 4 of 12	NP_003845.2
	IL1RL2	NM_001351446.2		c.437G>T	p.Cys146Phe	missense	Exon 4 of 12	NP_001338375.1	Q9HB29-1
	IL1RL2	NM_001351447.1		c.138+4143G>T		intron	N/A	NP_001338376.1	Q9HB29-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL1RL2	ENST00000264257.7	TSL:1 MANE Select	c.437G>T	p.Cys146Phe	missense	Exon 4 of 12	ENSP00000264257.2	Q9HB29-1
	IL1RL2	ENST00000441515.3	TSL:1	c.138+4143G>T		intron	N/A	ENSP00000413348.2	Q9HB29-2
	IL1RL2	ENST00000908896.1		c.644G>T	p.Cys215Phe	missense	Exon 4 of 12	ENSP00000578955.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		4.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-8.9	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.89		Loss of sheet (P = 0.0817)
MVP		1.0
MPC		0.81
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		0.94
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr2-102808528;